O⁶-[(4-methyl)benzyl]guanine | 129409-65-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: O⁶-[(4-methyl)benzyl]guanine
• 英文别名: 2-amino-6-[4-(methyl)benzyloxy]purine；O⁶-(p-methylbenzyl)guanine；O6-[4-(methyl)benzyl]guanine；O-6-p-methylbenzyl guanine；O-6-p-methylbenzylguanine；O6-(p-methylbenzyl)guanine；6-[(4-methylphenyl)methoxy]-7H-purin-2-amine
• CAS: 129409-65-0
• 化学式: C₁₃H₁₃N₅O
• 分子量: 255.279
• InChiKey: LTICVMSDFXJSRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  89.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  O⁶-[(4-methyl)benzyl]guanine 在 盐酸 、 potassium fluoride 、 甲烷磺酸 、 2,6-二叔丁基-4-甲基苯酚 、 双氧水 、 4-甲基苯磺酸吡啶 、 乙酸酐 、 potassium carbonate 、 potassium hydroxide 作用下， 以 甲醇 、 水 、 二甲基亚砜 、 甲苯 、 叔丁醇 为溶剂， 反应 151.0h， 生成 entecavir
  参考文献：
  名称：

  恩替卡韦中间体及其制备方法

  摘要：

  本发明公开了一种恩替卡韦中间体及其制备方法。本发明提供了一种恩替卡韦中间体化合物8的制备方法，其包括以下步骤：在溶剂中，酸性条件下，将化合物9进行脱除羟基保护基的反应，得到化合物8。本发明还提供了一种恩替卡韦中间体化合物9的制备方法，其包括以下步骤：在非质子有机溶剂中，碱性条件下，将化合物10与羟基保护试剂进行上羟基保护基的反应，得到化合物9。本发明的制备方法原料廉价易得，反应条件温和，产品收率较高。原子经济性好，环境友好，适合于工业化生产。

  公开号：

  CN104177398B
• 作为产物：
  描述：

  (4-甲基苯基)甲醇 、 1-(2-氨基-7H-嘌呤-6-基)-1-甲基吡咯烷鎓氯化物 在 potassium tert-butylate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以43%的产率得到O⁶-[(4-methyl)benzyl]guanine
  参考文献：
  名称：

  Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase by O⁶-Benzylguanine

  摘要：

  O-6-Benzylguanine is an irreversible inactivator of O-6-alkylguanine-DNA alkyltransferase currently in clinical trials to overcome alkyltransferase-mediated resistance to certain cancer chemotherapeutic alkylating agents. In order to produce more soluble alkyltransferase inhibitors, we have synthesized three aminomethyl-substituted O-6-benzylguanines and the three methyl analogs and found that the substitution of aminomethyl at the meta-position greatly enhances inactivation of alkyltransferase, whereas para-substitution has little effect and ortho-substitution virtually eliminates activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R-2) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED50) values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein.

  DOI：

  10.1021/jm800675p

文献信息

• Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability
  作者：Patrick-Denis St-Coeur、Marc Cormier、Veronique LeBlanc、Pier Morin、Mohamed Touaibia

  DOI：10.2174/1573406412666160710210907

  日期：2016.12.22

  Background: Glioblastoma multiforme (GBM) is often associated with a poor survival prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6- methylguanine DNA-methyltransferase (MGMT). Objectives: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to TMZ. Methods: Twenty-five O6-alkyl, O6-aryl and O6-substituted-aryl guanine analogs including nine novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the T98G GBM cells viability. Results: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24 emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog (19), bearing a p-nitrobenzyl moiety, reduced considerably the O6-methylguanine DNAmethyltransferase expression level. When combined with TMZ (1), which is used as first line treatment for brain tumors, compounds 19, 22, and 24 decreased T98G cellsproliferation by 32%, 68% and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further supporting the notion that this cell model is resistant to this alkylating agent. Conclusion: Overall, these results notably highlight a group of MGMT inhibitors that warrants further exploration in the development of therapeutic options to circumvent TMZ resistance in brain tumors.

  背景：胶质母细胞瘤（GBM）通常与患者的生存预后不良相关。主要原因似乎是患者对用于治疗该肿瘤的化疗药物替莫唑胺（TMZ）产生了获得性或固有的耐药性。迄今为止，最被认可的耐药途径是通过O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）进行的直接DNA修复途径。 目的：设计并合成一系列MGMT抑制剂，以增强GBM细胞对TMZ的敏感性。 方法：合成了二十五个O6-烷基、O6-芳基和O6-取代芳基鸟嘌呤类似物，包括九个新化合物，并对它们进行了表征、分子对接分析，并在T98G GBM细胞上测试了其细胞毒性。 结果：通过与MGMT的分子建模，新设计的化合物19、22和24成为最有前景的MGMT配体，并显示出适度的细胞毒性。含有对硝基苄基的鸟嘌呤类似物（19）显著降低了O6-甲基鸟嘌呤DNA甲基转移酶的表达水平。当与用于脑肿瘤一线治疗的TMZ（1）联合使用时，化合物19、22和24分别使T98G细胞的增殖减少了32%、68%和50%。TMZ（1）对这些细胞的增殖显示出微弱的影响，这进一步支持了这种细胞模型对这种烷基化剂具有耐药性的观点。 结论：总的来说，这些结果显著突出了一些值得进一步探索的MGMT抑制剂，以开发克服脑肿瘤中TMZ耐药性的治疗方案。
• 11C -LABELED O6 -BENZYLGUANINE, PET PROBE CAPABLE OF VISUALIZING O6 -METHYL GUANINE METHYL-TRANSFERASE ACTIVITY, AND PRODUCTION METHOD OF THE SAME
  申请人：NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY

  公开号：US20190308974A1

  公开（公告）日：2019-10-10

  An object of the invention is to provide a 11 C-labeled O 6 -benzylguanine capable of obtaining a PET image and a process for producing the same. The 11 C-labeled O 6 -benzylguanine of the invention is represented by the following chemical formula (a). The 11 C-labeled O 6 -benzylguanine is produced by: a coupling step of cross-coupling a methyl iodide labeled with 11 C and the following organotin compound (b) (R 1 represents an alkyl group, and R 2 and R 3 represent a leaving group which can be eliminated with a base.) in the presence of a palladium complex, a phosphine ligand, and cuprous halide in an aprotic lactam; and a desorption step of desorbing the leaving groups R 2 and R 3 of the coupling product obtained by the coupling step with a base.

  该发明的目的是提供一种能够获得PET图像的11C标记的O6-苄基鸟嘌呤以及其生产方法。该发明的11C标记的O6-苄基鸟嘌呤由以下化学式(a)表示。该发明的11C标记的O6-苄基鸟嘌呤通过以下步骤生产：在无水环酰胺中，在钯配合物、膦配体和卤化亚铜的存在下，通过交叉偶联11C标记的碘甲烷和以下的有机锡化合物(b)（其中R1代表烷基，R2和R3代表能够通过碱消除的离开基团）进行偶联步骤；以及通过碱脱除偶联步骤获得的偶联产物的离开基团R2和R3的脱附步骤。
• [EN] CYTOTOXIC TUBULYSIN COMPOUNDS FOR CONJUGATION<br/>[FR] COMPOSÉS DE TUBULYSINE CYTOTOXIQUES POUR LA CONJUGAISON
  申请人：TUBE PHARMACEUTICALS GMBH

  公开号：WO2015113760A1

  公开（公告）日：2015-08-06

  The present invention provides one or more compounds of formula (I) for conjugation to small molecules, polymers, peptides, proteins, antibodies, antibody fragments etc.

  本发明提供了一个或多个式(I)的化合物，用于与小分子、聚合物、肽、蛋白质、抗体、抗体片段等结合。
• A Convenient Procedure for the Synthesis of O⁶-Benzylguanine Derivatives by Phase Transfer Catalysis
  作者：Xuan Liu、Qi-Huang Zheng、Gary D. Hutchins、Xiangshu Fei、Leonard C. Erickson、Kathy D. Miller、Bruce H. Mock、Barbara E. Glick-Wilson、Wendy L. Winkle、K. Lee Stone、Kathy A. Carlson

  DOI：10.1081/scc-120016358

  日期：2003.1.4

  Abstract A convenient procedure by phase transfer catalysis has been developed for the synthesis of O6-BG (1) and its derivatives hydroxymethyl-BG (2a–c), halo-BG (3a–c, 4a–c, 5a–c, 6a–c), methoxy-BG (7), and methyl-BG (8). Compounds 2b, 2c, 4b, 4c, 5b, 5c, 6a, and 6c are new compounds.

  摘要 已经开发了一种方便的相转移催化方法用于合成 O6-BG (1) 及其衍生物羟甲基-BG (2a-c)、卤代-BG (3a-c, 4a-c, 5a-c, 6a -c)、甲氧基-BG (7) 和甲基-BG (8)。化合物 2b、2c、4b、4c、5b、5c、6a 和 6c 是新化合物。
• 11C -labeled 06 -benzylguanine, pet probe capable of visualizing 06-methyl guanine methyl-transferase activity, and production method of the same
  申请人：NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY

  公开号：US10981913B2

  公开（公告）日：2021-04-20

  An object of the invention is to provide a 11C-labeled O6-benzylguanine capable of obtaining a PET image and a process for producing the same. The 11C-labeled O6-benzylguanine of the invention is represented by the following chemical formula (a). The 11C-labeled O6-benzylguanine is produced by: a coupling step of cross-coupling a methyl iodide labeled with 11C and the following organotin compound (b) (R1 represents an alkyl group, and R2 and R3 represent a leaving group which can be eliminated with a base) in the presence of a palladium complex, a phosphine ligand, and cuprous halide in an aprotic lactam; and a desorption step of desorbing the leaving groups R2 and R3 of the coupling product obtained by the coupling step with a base.

  本发明的目的是提供一种能够获得 PET 图像的 11C 标记 O6-苄基鸟嘌呤及其生产工艺。 本发明的 11C 标记 O6-苄基鸟嘌呤由以下化学式（a）表示。 11C 标记的 O6-苄基鸟嘌呤是通过以下方法制得的：在钯络合物、膦配体和卤化亚铜的存在下，在非沸腾内酰胺中，将标记有 11C 的甲基碘和下列有机锡化合物（b）（R1 代表烷基，R2 和 R3 代表可使用碱消除的离去基团）进行交叉偶联的偶联步骤；以及使用碱对偶联步骤得到的偶联产物的离去基团 R2 和 R3 进行解吸的解吸步骤。